The present invention relates to treating or preventing a disease or condition involving platelet aggregation. The method includes administering a pharmaceutically effective amount of a compound that inhibits platelet aggregation and more particularly inhibits collagen-induced platelet aggregation.
Heart disease, a common cause of death in today""s society, is often a result of ischemic and/or thromboembolic events or syndromes including myocardial infarction, chronic unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis and/or thrombosis following angioplasty, carotid endarterectomy, anastomosis of vascular grafts and other cardiovascular devices. These events and syndromes represent a variety of stenotic and occlusive vascular disorders involving platelet aggregation on vessel walls or within the lumen.
The basic mechanism of platelet aggregation has been well studied. The mechanism starts with a blood vessel injury such as narrowing of the lumen, plaque formation, or the presence of foreign bodies/medical instruments. This injury leads to platelet activation and binding of fibrinogen and ligands.
Platelet binding via the surface xcex12xcex21 integrin and glycoproteins GPVI to the extracellular matrix protein collagen from exposed subendothelium at sites of vascular injury initiates a tyrosine kinase-dependent signal transduction cascade leading to platelet activation, degranulation, aggregation, and formation of a hemostatic thrombus (Gibbins et al., (1997) FEBS Lett, 413:255-91; Moroi, M. and Jung, S. M., (1997) Thromb Haemost 78:439-444; Quek, et al. (1998) Curr Biol, 8:1137-1140; Tsuji, et al., (1997) J Biol Chem 272:23528-23531).
Bruton""s tyrosine kinase (BTK), a member of the BTK/Tec family of protein tyrosine kinases (PTKs), is a cytoplasmic PTK involved in signal transduction pathways regulating growth and differentiation of B-lineage lymphoid cells (Rawlings, D. J., and Witte, O. N. (1994) Immunol. Rev. 138, 105-119; Kurosaki, T. (1997) Curr Opin. Immunol. 9, 309-318; and Uckun, F. M. (1998) Biochemical Pharmacology, et al., 56, 683-691). BTK participates in signal transduction pathways initiated by the binding of a variety of extracellular ligands to their cell surface receptors. Following ligand binding of B cell antigen receptors (BCR), BTK activation by the concerted actions of the PTKs Lyn and Syk (Kurosaki, T. (1997) Curr Opin. Immunol. 9, 309-318) is required for induction of phospholipase C-xcex32 mediated calcium mobilization (Kurosaki, T. (1997) Curr Opin. Immunol. 9, 309-318).
BTK participates in the collagen receptor glycoprotein VI (GP VI)-Fc receptor gamma (FcRxcex3) chain coupled signaling. Tyrosine phosphorylation of the immune-receptor tyrosine based activation motif (ITAM) of the FcRxcex3 chain leads to phosphorylation and activation of phospholipase C gamma 2 (PLCxcex32). Activated PLCxcex32 converts PI-4,5-bisphospate (PIP2) to inositol triphosphate (IP3), leading to intracellular calcium mobilization.
Gelotte, U.S. Pat. No. 5,972,967 and Scarborough, et al. U.S. Pat. No. 5,968,902 have described certain compounds and compositions that inhibit binding to a platelet by limiting the binding of fibrinogen. Nevertheless, there still is a need for finding compounds and improved methods to treat or prevent a condition of platelet aggregation.
In accordance with the purpose(s) of this invention, as embodied and broadly described herein, this invention, in one aspect, relates to a method for inhibiting platelet aggregation by administering an effective amount of a compound of the formula: 
or a pharmaceutically acceptable acid addition salt thereof.
In a second aspect, the invention relates to a method of preventing or treating a disease or condition involving platelet aggregation in a subject comprising administering to a subject an effective amount of a compound of the formula: 
or a pharmaceutically acceptable acid addition salt thereof.
Additional advantages of the invention will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
The accompanying drawings that are incorporated in and constitute a part of this specification illustrate several experimental examples and together with the description, serve to explain the principles of the invention.